Sirolimus Treatment in Patients With Autosomal Dominant Polycystic Kidney Disease: Renal Efficacy and Safety
Status:
Completed
Trial end date:
2009-08-01
Target enrollment:
Participant gender:
Summary
Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal
disease, characterized by the progressive development of fluid-filled cysts in the kidney
leading to progressive loss of renal function and eventually to renal failure. It is
responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western
countries. ADPKD progression is largely dependent on the development and growth of the cysts
and secondary disruption of the normal tissue. Renoprotective interventions in ADPKD - in
addition to achieve maximal reduction of arterial blood pressure and proteinuria and to limit
the effects of additional potential promoters of disease progression such as dyslipidemia,
chronic hyperglycemia or smoking - should also be specifically aimed to correct the
dysregulation of epithelial cell growth, secretion, and matrix interactions characteristic of
the disease. Genetically in the ADPKD three different genes are implicated (PKD1 85% of the
cases, PKD2 15% and probably PDK3 not yet identified). PKD1 gene encodes a protein named
polycystin-1 (PC1). Defect in PC1 lead to aberrant activation of the enzyme mTOR in the
epithelial cells of the renal tubules which eventually leads to abnormal proliferation of
these cells and cysts generation.
Sirolimus (Rapamycin) is an immunosuppressant mostly used for the management of kidney
transplant recipients. This drug by very specifically and effectively inhibiting mTOR, exerts
antiproliferative and growth inhibiting effects and could be extremely important for the
inhibition of cyst progression in ADPKD. Animal models of ADPKD have shown that short-term
treatment with sirolimus resulted in dramatic reduction of kidney size, prevented the loss of
kidney function, and lowered cyst volume density. Similarly, retrospective observations from
kidney transplant recipients have documented that sirolimus treatment reduced kidney volumes
by 25%, whereas there was no effect in patients not given the drug.
Overall, these findings provide the basis for designing a prospective study in ADPKD patients
aimed to document the efficacy of sirolimus treatment in preventing further increase or even
reducing the total kidney volume and the renal volume taken up by small cysts, eventually
halting kidney disease progression. It is a 6 month treatment with sirolimus compared to
conventional therapy in adult patients with ADPKD and normal renal function or mild to
moderate renal insufficiency.
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research